Hormone intermediates and preparation of same



Patented Oct. 15, 1946 HORMONE INTERNIEDIATES AND PREP- ARATION F SAlVlE Russell Earl Marker, MexicoCity, Mexico, assignor to Parke, Davis 8; Company, Detroit, Mich, a corporation of Michigan No Drawing. Original application June 30, 1941,

Serial No. 400,559. Divided and this application May 24, 1944, Serial No. 537,201

This invention relates to the preparation of certain hormone intermediates, and this application is a division of my copending application, Serial No. 400,559, filed June 30, 1941, now Patent No. 2,352,648, issued July 4, 1944.

In my copending application, Serial No. 393,- 667, filed May 15, 1941, now Patent No. 2,352,852, issued July 4, 1944, it is shown that steroidal sapogenins can be converted into a new class of compounds which I designate as pseudo-sapogenins including pseudo-sapogenin eXo-acylates.

In my copending application, Serial No. 382,- 451, filed March 8, 1941, now Patent No. 2,352,850, issued July 4, 1944, it is shown that diosgenin may be converted into pseudo-diosgenin diacetate.

In the copending application of Marker, Crooks & Wittle, Serial No. 393,666, filed May 15, 1941, now Patent No. 2,352,851, issued July 4, 1944, there is described the oxidation of pseudo-sapogenin exo-acylates to give a new class of esters designated 20-keto-16-(e-acyloxy-isocaprooxy)- pregnane compounds represented by the partial formula CHa In my Patent No. 2,352,648, I have described 5 Claims. (C1, 260-397.4)

ll CHz-C- other substance containing reactive hydrogen,

CH3 1H OHM) Where the term 20-(a) -hydroxy occurs in this specification, it will be understood that this term refers to one of the two epimers theoretically possible. See further R. E. Marker et al., J. Am. Chem. Soc., 59, 2291 (1937).

My invention may be illustrated by the following examples.

(a) Diosgenin is treated as set forth more fully in my copending Patent No. 2,352,850 for six to fifteen hours with acetic anhydride at 200 0., thereby forming pseudo-diosgenin diacetate. After crystallization from methanol, the pseudo-diosgenin diacetate has a melting point of 97-100" 0.

(b) Pseudo-diosgenin diacetate is oxidized with chromic anhydride in acetic acid at 28 0., as set forth more fully in the copending Patent No. 2,352,851. Thus there is obtained the corresponding 20 keto l6 (6-acyloxy-isocaprooxy) pregnane compound of melting point -86 C. This compound is believed to have the structure,

and it may be designated as A -pregnenediol- 3(5) ,16 one 20 3 acetate-l6-(a-acetoxy) -isocaproate.

(c) To 2 g. of the product, melting point 85-86 0., designated as A -pregnenediol-3-(B) ,16-one- 20 3-acetate-16-(6-acetoxy) -isocaproate, in 200 cc. of dry isopropyl alcohol is added 15 g. of sodium in small pieces. The mixture is refluxed for about an hour or until all the sodium has been dissolved. Thereupon water is added and the mixture extracted well with ether. The ethereal layer is washed with water and then the ether is removed on a steam bath. The residue is crystallized from dilute acetone and from dilute methanol and thus yields A -pregnenedio1-3-(fi) ,20- (a) of melting point 171-176 C.

The structure of the above product is shown by 5 the fact that it may :be hydrogenated in the presence of glacial acetic acid and a platinum oxide catalyst to yield allo-pregnanediol-B-(fl),ZO-(u) of melting point 214-216 C.

The above examples are intended to illustrate but not to limit the scope of my invention. Other modes of employing my processapparent to those skilled in the art after this disclosure, are, intended to fall within the scope of my invention and accordingly I wish to limit the scope of my invention only as indicated in the appended claims.

What I claim as my invention is:

1. Process for preparing hydroxy-pregnane derivatives which comprise subjecting a steroid having in ring D the structure CH3 I o CH3 C= D I CH:

to the action of an alkali metal in combination with an alcohol reactive with said alkali metal to form nascent hydrogen, thereby producing a steroid having in ring D the structure CH: cm. on one! D l 2. Process for preparing hydroxy-pregnane derlvatives which comprises subjecting a steroid of the formula where 71A represents 11 carbon-to-carbon double bonds between C5 and C5, 11 having one of the values 0 and 1, and Y is a member of the class consisting of hydroxyl and groups hydrolyzable to hydroxyl, to the action of an alkali metal in combination with an alcohol reactive with said alkali metal to form nascent hydrogen, thereby producing a steroid of the formula 3. Process for preparing hydroxy-pregnane derivatives which comprises subjecting a steroid of the formula CH3 CH3 (I) OH: 2- 2- H:- -acy 0 J CH CH (EHO O l where Y is a member of the class consisting of hydroxyl and groups hydrolyzable to hydroxyl, to the action of an alkali metal in combination with an alcohol reactive With said alkali metal to form nascent hydrogen, thereby producing a steroid of the formula CHa CH: OH:

H OHM) I V 4. Process for preparing A -pregnenediol3- 3),20-(u) which comprises subjecting A -pregnenediol 3-(5) 6-one-20 3-acetate-16-(6-acetoxy)-isocaproate to the action of a alkali metal in combination with an alcohol reactive with said alkali metal to form nascent hydrogen.

5. Process for preparing A -pregnenediol-3- (,B), (a) which comprises subjecting A -pregnenediol 3-(p),16-one-20 3-acetate-l6-(6-acetoxy) -isocaproate to the action of sodium and isopropyl alcohol.

RUSSELL EARL MARKER. 

